岩藻糖基化
下调和上调
细胞生物学
癌症研究
Notch信号通路
信号转导
生物
小干扰RNA
化学
细胞培养
分子生物学
岩藻糖
生物化学
转染
基因
遗传学
糖蛋白
作者
Cindy E Ament,Sara Steinmann,Katja Evert,Giovanni Mario Pes,Silvia Ribback,Isabella Gigante,Elena Antinoro Pizzuto,Jesús M. Bañales,Pedro M. Rodrigues,Paula Olaizola,Haichuan Wang,Gianluigi Giannelli,Xin Chen,Matthias Evert,Diego F. Calvisi
出处
期刊:Hepatology
[Wiley]
日期:2023-02-16
卷期号:78 (6): 1742-1754
被引量:2
标识
DOI:10.1097/hep.0000000000000322
摘要
Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy, with increasing incidence worldwide and limited therapeutic options. Aberrant protein glycosylation is a hallmark of cancer. Here, we thoroughly investigated the possible involvement of fucosylation in cholangiocarcinogenesis.We discovered that the levels of global fucosylation and members of the fucosylation pathway are ubiquitously upregulated in human iCCA tissues compared to nontumorous surrounding livers and normal biliary cells. In addition, total fucosylation levels correlate with poor patients' prognosis. Furthermore, fucosylation inhibition following 6-alkynylfucose (6AF) administration triggered a dose-dependent decrease in the proliferation and migration of iCCA cell lines. Notably, adding fucose to the cell medium annulled these effects. At the molecular level, 6AF administration or small interfering RNA-mediated silencing of GDP-L-fucose synthetase (FX) and the GDP-fucose transmembrane transporter (SLC35C1), both pivotal players of cellular fucosylation, decreased NOTCH activity, NOTCH1/Jagged1 interaction, NOTCH receptors, and related target genes in iCCA cell lines. In the same cells, EGFR, nuclear factor kappa-light-chain-enhancer of activated B cells p65, and Bcl-xL protein levels diminished, whereas IκBα (a critical cellular NF-κB inhibitor) increased after FX/SLC35C1 knockdown or 6AF administration. In the chick chorioallantoic membrane assay, 6AF treatment profoundly suppresses the growth of iCCA cells.Elevated global fucosylation characterizes human iCCA, contributing to cell growth and migration through the upregulation of the NOTCH and EGFR/NF-κB pathways. Thus, aberrant fucosylation is a novel pathogenetic player and a potential therapeutic target for human iCCA.
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